The drug development industry is notoriously conservative. Quite understandably it is reluctant to take risks in clinical trials that may put patients’ lives in danger. The result of this has been a trial cycle that is long, expensive and very often unsuccessful.
It is testament to the advantages adaptive trials offer, therefore, that their adoption has become so widespread in a relatively short space of time in an industry that can often move slowly when it comes to change.
In a number of Arena International events later in 2009 industry leaders will debate the challenges they face in designing trials to ensure their effectiveness, minimise costs and maximise returns.
The conferences focus on clinical areas such as paediatric drug development, oncology and exploratory trials. What is likely to be an overarching theme in each is how adapting trials during their development offers dramatic advantages and complex operational challenges.
An adaptive trial is exactly as it sounds. Instead of a trial being split into strict differentiated sections, data is collected from the very beginning and analysed throughout to shape the future design of the trial.
Technological advancements have meant that data can be sourced much quicker than before and shared with data handlers around the world almost instantaneously. This fast knowledge transfer means that efficacy and toxicity can be analysed as events occur, increasing patient safety and allowing a development firm to “kill” a compound quicker if it looks to be unsuccessful.
Adapting to the advantages
Pushing the growth of adaptive trials is the increasingly complex nature of disease mutations, drugs and trial designs. Roche translational medicine leader Pavel Pisa is focused on oncology compounds where the use of adaptive trials has exploded. “It is the complex nature of the disease, the heterogeneity of the patient population and the specificity of the drug [that makes adaptive trials well suited to oncology],” he says.
This field of clinical research rarely involves healthy volunteers and often focuses on cancer patients. In these cases, Pisa says that trials are held in sites where the investigator is already familiar with the family of drugs in which the new compound may sit and they are therefore very receptive with moving the trial forward as fast as possible.
“For the investigators it is interesting to participate in an adaptive trial design because it is more scientific. I think it is appealing a lot to the investigators so they are they are motivated to explain it to the patient,” Pisa adds.
Adaptive trials are also allowing trial subjects to be used more efficiently. This means fewer subjects need to be recruited and exposed to drugs that are yet to be approved, which in turn saves money for the drug development firm.
“I don’t think it is acceptable to expose patients to doses below therapeutic levels needlessly so we are using an adaptive trial design for the escalation of patients,” Pisa says.
When a dosage is beginning to show molecular efficacy and is therefore hinting that it could show clinical efficacy but it is still tolerated in the subject the trial is then expanded. “With an adaptive trial design we don’t have to wait for a clinical response to know that we have inhibited the target,” Pisa adds. “We can see quickly whether it has clinical benefit and start expanding the trial.”
By adapting key variables as the trial progresses, an adaptive trial design can bring down the length of a trial. In addition, although the complexity of the Phase I section is heightened – and therefore costs will be increased – the overall expense of the trial is brought down.
There are immense advantages to be garnered if the fierce operational challenges can be overcome. Any change to a clinical trial once it is underway will affect an almost insurmountable number of people and procedures. Changing the trial design will result in altering data capture methods and collection, what and how symptoms displayed by subjects are monitored and how the drugs are supplied to patients around the world.
For Pisa, it is the last point that often results in difficulties. As the number of subjects is decreased, trials tend to be made up of smaller investigational sites with only one or two patients being studied that display the particular clinical results.
Even where the subject numbers are minimal, the costly and time-consuming practice of overcoming the regulatory hurdles to import the dosage supply still needs to be carried out – a factor that can deter smaller investigational sites from participating in the trial. Pisa says that this means the supply operation has to become more flexible and drugs need to be in place to be shipped much earlier.
In addition, educating particular regulators in how adaptive trials work is another battle for pharmaceutical companies. “In some countries the ethics committees say that a Phase I and Phase II trial can not be run at the same time but I really hope these hurdles will be overcome because [the advantages] are not only for the company but for the patients,” Pisa says.
He adds, however, that despite the complexities, clinical trials will increasingly move towards having an adaptive trial design. “I think they are here to stay, I can not imagine that trials will go in another direction,” Pisa concludes.
A number of Arena International events are focusing on clinical trials in the coming months. These include the Third Annual Adaptive Trials and Exploratory Clinical Trials conferences on 8–9 December in Brussels, Belgium; Clinical Trials in Oncology on 1-2 December in Munich, Germany and the Paediatric Drug Development and Clinical Trials on 17–18 November in Brussels, Belgium.